rs45506801

Variant names:

• chr17-82085337-G-A
• rs45506801
• NM_004104.5:c.4188C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_004104.5(FASN):​c.4188C>T​(p.Tyr1396Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00167 in 1,611,624 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0088 (13 hom., cov: 34)
  • Exomes 𝑓: 0.00092 (11 hom.)
• Consequence: FASN NM_004104.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.167
• Publications: 1 publications found

Genes affected

FASN (HGNC:3594): (fatty acid synthase) The enzyme encoded by this gene is a multifunctional protein. Its main function is to catalyze the synthesis of palmitate from acetyl-CoA and malonyl-CoA, in the presence of NADPH, into long-chain saturated fatty acids. In some cancer cell lines, this protein has been found to be fused with estrogen receptor-alpha (ER-alpha), in which the N-terminus of FAS is fused in-frame with the C-terminus of ER-alpha. [provided by RefSeq, Jul 2008]

FASN Gene-Disease associations (from GenCC):

• neurodevelopmental disorder

  Inheritance: AR Classification: LIMITED Submitted by: G2P

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 17-82085337-G-A is Benign according to our data. Variant chr17-82085337-G-A is described in ClinVar as Benign. ClinVar VariationId is 462052.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.167 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00877 (1336/152312) while in subpopulation AFR AF = 0.0303 (1261/41574). AF 95% confidence interval is 0.0289. There are 13 homozygotes in GnomAd4. There are 649 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 13 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004104.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FASN	NM_004104.5	MANE Select	c.4188C>T	p.Tyr1396Tyr	synonymous	Exon 24 of 43	NP_004095.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FASN	ENST00000306749.4	TSL:1 MANE Select	c.4188C>T	p.Tyr1396Tyr	synonymous	Exon 24 of 43	ENSP00000304592.2	P49327
	FASN	ENST00000940344.1		c.4215C>T	p.Tyr1405Tyr	synonymous	Exon 24 of 43	ENSP00000610403.1
	FASN	ENST00000940346.1		c.4212C>T	p.Tyr1404Tyr	synonymous	Exon 24 of 43	ENSP00000610405.1

Frequencies

GnomAD3 genomes AF: 0.00871 AC: 1325 AN: 152194 Hom.: 13 Cov.: 34

Gnomad AFR AF: 0.0302

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00373

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00621

GnomAD2 exomes AF: 0.00229 AC: 556 AN: 242364 AF XY: 0.00179

Gnomad AFR exome AF: 0.0325

Gnomad AMR exome AF: 0.00135

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000830

Gnomad OTH exome AF: 0.00136

GnomAD4 exome AF: 0.000924 AC: 1349 AN: 1459312 Hom.: 11 Cov.: 71 AF XY: 0.000851 AC XY: 618 AN XY: 725870

African (AFR) AF: 0.0332 AC: 1111 AN: 33456

American (AMR) AF: 0.00166 AC: 74 AN: 44612

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26092

East Asian (EAS) AF: 0.00 AC: 0 AN: 39636

South Asian (SAS) AF: 0.0000581 AC: 5 AN: 86114

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51818

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5744

European-Non Finnish (NFE) AF: 0.0000405 AC: 45 AN: 1111542

Other (OTH) AF: 0.00179 AC: 108 AN: 60298

GnomAD4 genome AF: 0.00877 AC: 1336 AN: 152312 Hom.: 13 Cov.: 34 AF XY: 0.00871 AC XY: 649 AN XY: 74472

African (AFR) AF: 0.0303 AC: 1261 AN: 41574

American (AMR) AF: 0.00372 AC: 57 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68008

Other (OTH) AF: 0.00614 AC: 13 AN: 2116

Alfa AF: 0.00759 Hom.: 6

Bravo AF: 0.0102

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Epileptic encephalopathy (1)
-	-	1	FASN-related disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	1.2
DANN	Benign	0.93
PhyloP100		0.17
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs45506801; hg19: chr17-80043213;